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Odanacatib reduced fractures but upped stroke risk
The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.
Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.
Compared with placebo, odanacatib resulted in relative risk reductions of 52% for vertebral fracture, 48% for hip fracture, 26% for nonvertebral fracture, and 67% for clinical vertebral fracture (all values, P less than .001). Lumbar spine bone density increased by a mean of 10.9%, as did total hip bone density by a mean of 10.3%, in the odanacatib group (for both, P less than .001), according to results presented at the meeting.
The Long-Term Odanacatib Fracture Trial (LOFT) was a randomized, double-blind placebo-controlled study that investigated the efficacy and safety of odanacatib, a cathepsin K inhibitor, as a treatment for osteoporosis and for fracture prevention in postmenopausal women. Odanacatib was taken as an oral, once-weekly 50-mg pill.
During the base period of the study, 16,071 postmenopausal women aged 65 and older were enrolled, and 12,290 completed the study. Women had to have total hip or femoral neck bone mineral density T scores less than or equal to –2.5, or a radiographically confirmed vertebral fracture and total hip or femoral neck T scores less than or equal to –1.5. Participants were demographically well matched between study arms; 6,092 odanacatib patients and 6,198 on placebo completed the base period of the study.
The original phase III study was stopped early because of robust efficacy data (Osteoporos Int. 2015 Feb;26[2]:699-712). Participants were eligible to continue in a preplanned 5-year double-blind, placebo-controlled extension period of the LOFT study; 3,432 odanacatib and 2,615 placebo participants completed the full 5 years.
An early, but statistically nonsignificant, signal for increased stroke and atrial fibrillation and flutter was seen at the end of the study’s base period. The trend continued and appeared to be amplified during the 5-year, double-blind, placebo-controlled extension period of the LOFT study.
In an interview, Dr. O’Donoghue said that the TIMI study group was brought in by Merck for a “second perspective,” to add rigor to an examination of events that had not been anticipated in the base period of the LOFT study. This was an important step, said Dr. O’Donoghue, because LOFT was not a dedicated cardiovascular safety trial.
The prespecified primary endpoints for TIMI’s safety analysis included new-onset atrial flutter or atrial fibrillation, as well as a composite endpoint of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or cardiovascular death.
Examination of the composite MACE endpoint showed a numeric, but not statistically significant, difference between the odanacatib and placebo arms of the extension study. However, in a preplanned subanalysis, when the 324 stroke events were isolated, a hazard ratio (HR) for stroke of 1.37 for odanacatib emerged (95% confidence interval [CI], 1.10-1.71; P = .005).
Atrial fibrillation and atrial flutter were more common in the odanacatib group, but the difference was not significant (HR, 1.22; 95% CI, 0.99-1.50; P = .06). Dr. O’Donoghue said that the individuals with supraventricular arrhythmias were not the same individuals who had strokes, although the strokes were almost entirely ischemic, rather than hemorrhagic, events.
Dr. O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital, noted in her presentation that “preclinical data suggested that inhibition of cathepsin K may reduce atherosclerosis progression and promote plaque stability.”
Odanacatib is a cathepsin K inhibitor, one of a member of a class of proteases. Cathepsin K targets kinins that are involved in bone resorption, but it is expressed in other tissues as well, and it may target other classes of kinins. However, exactly how odanacatib may have contributed to strokes in the study population remains a mystery.
“The mechanistic underpinnings to explain these findings is unknown and warrants investigation,” Dr. O’Donoghue said. “It’s a little bit more unsatisfying when you’re not able to provide a cause. … I share the disappointment of the endocrinologists in the community who were very hopeful for the cathepsin K class to be the next breakthrough in the management of osteoporosis.”
Dr. McClung reported financial relationships with Merck and several other pharmaceutical companies. Dr. O’Donoghue reported receiving grant support from several pharmaceutical companies. The LOFT trial and the TIMI study group analysis were sponsored by Merck.
koakes@frontlinemedcom.com
On Twitter @karioakes
The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.
Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.
Compared with placebo, odanacatib resulted in relative risk reductions of 52% for vertebral fracture, 48% for hip fracture, 26% for nonvertebral fracture, and 67% for clinical vertebral fracture (all values, P less than .001). Lumbar spine bone density increased by a mean of 10.9%, as did total hip bone density by a mean of 10.3%, in the odanacatib group (for both, P less than .001), according to results presented at the meeting.
The Long-Term Odanacatib Fracture Trial (LOFT) was a randomized, double-blind placebo-controlled study that investigated the efficacy and safety of odanacatib, a cathepsin K inhibitor, as a treatment for osteoporosis and for fracture prevention in postmenopausal women. Odanacatib was taken as an oral, once-weekly 50-mg pill.
During the base period of the study, 16,071 postmenopausal women aged 65 and older were enrolled, and 12,290 completed the study. Women had to have total hip or femoral neck bone mineral density T scores less than or equal to –2.5, or a radiographically confirmed vertebral fracture and total hip or femoral neck T scores less than or equal to –1.5. Participants were demographically well matched between study arms; 6,092 odanacatib patients and 6,198 on placebo completed the base period of the study.
The original phase III study was stopped early because of robust efficacy data (Osteoporos Int. 2015 Feb;26[2]:699-712). Participants were eligible to continue in a preplanned 5-year double-blind, placebo-controlled extension period of the LOFT study; 3,432 odanacatib and 2,615 placebo participants completed the full 5 years.
An early, but statistically nonsignificant, signal for increased stroke and atrial fibrillation and flutter was seen at the end of the study’s base period. The trend continued and appeared to be amplified during the 5-year, double-blind, placebo-controlled extension period of the LOFT study.
In an interview, Dr. O’Donoghue said that the TIMI study group was brought in by Merck for a “second perspective,” to add rigor to an examination of events that had not been anticipated in the base period of the LOFT study. This was an important step, said Dr. O’Donoghue, because LOFT was not a dedicated cardiovascular safety trial.
The prespecified primary endpoints for TIMI’s safety analysis included new-onset atrial flutter or atrial fibrillation, as well as a composite endpoint of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or cardiovascular death.
Examination of the composite MACE endpoint showed a numeric, but not statistically significant, difference between the odanacatib and placebo arms of the extension study. However, in a preplanned subanalysis, when the 324 stroke events were isolated, a hazard ratio (HR) for stroke of 1.37 for odanacatib emerged (95% confidence interval [CI], 1.10-1.71; P = .005).
Atrial fibrillation and atrial flutter were more common in the odanacatib group, but the difference was not significant (HR, 1.22; 95% CI, 0.99-1.50; P = .06). Dr. O’Donoghue said that the individuals with supraventricular arrhythmias were not the same individuals who had strokes, although the strokes were almost entirely ischemic, rather than hemorrhagic, events.
Dr. O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital, noted in her presentation that “preclinical data suggested that inhibition of cathepsin K may reduce atherosclerosis progression and promote plaque stability.”
Odanacatib is a cathepsin K inhibitor, one of a member of a class of proteases. Cathepsin K targets kinins that are involved in bone resorption, but it is expressed in other tissues as well, and it may target other classes of kinins. However, exactly how odanacatib may have contributed to strokes in the study population remains a mystery.
“The mechanistic underpinnings to explain these findings is unknown and warrants investigation,” Dr. O’Donoghue said. “It’s a little bit more unsatisfying when you’re not able to provide a cause. … I share the disappointment of the endocrinologists in the community who were very hopeful for the cathepsin K class to be the next breakthrough in the management of osteoporosis.”
Dr. McClung reported financial relationships with Merck and several other pharmaceutical companies. Dr. O’Donoghue reported receiving grant support from several pharmaceutical companies. The LOFT trial and the TIMI study group analysis were sponsored by Merck.
koakes@frontlinemedcom.com
On Twitter @karioakes
The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.
Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.
Compared with placebo, odanacatib resulted in relative risk reductions of 52% for vertebral fracture, 48% for hip fracture, 26% for nonvertebral fracture, and 67% for clinical vertebral fracture (all values, P less than .001). Lumbar spine bone density increased by a mean of 10.9%, as did total hip bone density by a mean of 10.3%, in the odanacatib group (for both, P less than .001), according to results presented at the meeting.
The Long-Term Odanacatib Fracture Trial (LOFT) was a randomized, double-blind placebo-controlled study that investigated the efficacy and safety of odanacatib, a cathepsin K inhibitor, as a treatment for osteoporosis and for fracture prevention in postmenopausal women. Odanacatib was taken as an oral, once-weekly 50-mg pill.
During the base period of the study, 16,071 postmenopausal women aged 65 and older were enrolled, and 12,290 completed the study. Women had to have total hip or femoral neck bone mineral density T scores less than or equal to –2.5, or a radiographically confirmed vertebral fracture and total hip or femoral neck T scores less than or equal to –1.5. Participants were demographically well matched between study arms; 6,092 odanacatib patients and 6,198 on placebo completed the base period of the study.
The original phase III study was stopped early because of robust efficacy data (Osteoporos Int. 2015 Feb;26[2]:699-712). Participants were eligible to continue in a preplanned 5-year double-blind, placebo-controlled extension period of the LOFT study; 3,432 odanacatib and 2,615 placebo participants completed the full 5 years.
An early, but statistically nonsignificant, signal for increased stroke and atrial fibrillation and flutter was seen at the end of the study’s base period. The trend continued and appeared to be amplified during the 5-year, double-blind, placebo-controlled extension period of the LOFT study.
In an interview, Dr. O’Donoghue said that the TIMI study group was brought in by Merck for a “second perspective,” to add rigor to an examination of events that had not been anticipated in the base period of the LOFT study. This was an important step, said Dr. O’Donoghue, because LOFT was not a dedicated cardiovascular safety trial.
The prespecified primary endpoints for TIMI’s safety analysis included new-onset atrial flutter or atrial fibrillation, as well as a composite endpoint of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or cardiovascular death.
Examination of the composite MACE endpoint showed a numeric, but not statistically significant, difference between the odanacatib and placebo arms of the extension study. However, in a preplanned subanalysis, when the 324 stroke events were isolated, a hazard ratio (HR) for stroke of 1.37 for odanacatib emerged (95% confidence interval [CI], 1.10-1.71; P = .005).
Atrial fibrillation and atrial flutter were more common in the odanacatib group, but the difference was not significant (HR, 1.22; 95% CI, 0.99-1.50; P = .06). Dr. O’Donoghue said that the individuals with supraventricular arrhythmias were not the same individuals who had strokes, although the strokes were almost entirely ischemic, rather than hemorrhagic, events.
Dr. O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital, noted in her presentation that “preclinical data suggested that inhibition of cathepsin K may reduce atherosclerosis progression and promote plaque stability.”
Odanacatib is a cathepsin K inhibitor, one of a member of a class of proteases. Cathepsin K targets kinins that are involved in bone resorption, but it is expressed in other tissues as well, and it may target other classes of kinins. However, exactly how odanacatib may have contributed to strokes in the study population remains a mystery.
“The mechanistic underpinnings to explain these findings is unknown and warrants investigation,” Dr. O’Donoghue said. “It’s a little bit more unsatisfying when you’re not able to provide a cause. … I share the disappointment of the endocrinologists in the community who were very hopeful for the cathepsin K class to be the next breakthrough in the management of osteoporosis.”
Dr. McClung reported financial relationships with Merck and several other pharmaceutical companies. Dr. O’Donoghue reported receiving grant support from several pharmaceutical companies. The LOFT trial and the TIMI study group analysis were sponsored by Merck.
koakes@frontlinemedcom.com
On Twitter @karioakes
FROM THE NAMS 2016 ANNUAL MEETING
Early menopause a risk factor for type 2 diabetes
“What we see in our data is that indeed, early onset of menopause is associated with increased risk of type 2 diabetes, and this association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also of estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, in an interview.
Dr. Muka, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands, presented the analysis from a large, prospective cohort of menopausal women at the annual meeting of the North American Menopause Society.
In an interview, Dr. Muka noted that the study investigated whether the association between early age at natural menopause (ANM) and type 2 diabetes is independent of intermediate risk factors for type 2 diabetes, such as obesity. Finally, the study also assessed whether endogenous sex hormone levels play a role in the link between early ANM and type 2 diabetes.
Enrollment in the Rotterdam study has been continuing in waves since the 1990s, with enrollment for participants in this particular study cohort occurring in 1997 and with additional cohorts enrolled in 2000-2001 and 2006-2008.
“I think this is the first prospective study with such long follow-up data and with a broad adjustment for confounding factors. Previous studies have been mainly cross-sectional, providing conflicting results,” said Dr. Muka.
Using self-reported age at menopause, the investigators excluded from the study women whose menopausal status was not known, who were actually not menopausal, or whose menopause had not occurred naturally. The study population also excluded women with prevalent type 2 diabetes or for whom no information about diabetes follow-up could be found.
The remaining 3,210 women who were included in the study had a median age of 67 years and had reached menopause at a median of 49.9 years. Most women (82.6%) had an ANM of 45-55 years; ANM for 8.8% was 40-44 years, while just 2.3% had an ANM of under 40 years. Mean body mass index was 27.1 kg/m2.
Participants were considered to have incident diabetes based on several sources: a general practitioner’s records, hospital discharge paperwork, or glucose measurements from visits during the Rotterdam study. Participants also were classified as having diabetes if they used a hypoglycemic medication or had a fasting blood glucose level of at least 7 mmol/L (126 mg/dL) or, in the absence of a fasting blood glucose measurement, a nonfasting blood glucose of at least 11.1 mmol/L (200 mg/dL).
Dr. Muka said he and his coinvestigators identified and adjusted for a large number of variables, using a series of three Cox proportion hazard models.
The first model adjusted for age, which wave of enrollment (cohort) participants were in, hormone therapy status, age at menarche, and the number of pregnancies that reached at least 6 months’ gestation.
The second model used all of the factors in model 1, and added BMI and glucose and insulin levels. The third model used all of the factors in model 2, and also added total cholesterol level, systolic blood pressure, the use of lipid-lowering or antihypertensive medications, alcohol and tobacco use, educational level, prevalent cardiovascular disease, and C-reactive protein levels.
The association of early ANM with the risk of type 2 diabetes was statistically significant in all three models (P less than .001), with very similar hazard ratios (HRs) in all models. For the third, the most comprehensive model, the HR was 1.42 (95% confidence interval, 0.83-2.45).
Extensive sensitivity analyses were carried out, and the association held independent of physical activity level, smoking status, use of hormone therapy, and age. The investigators also used multivariable analyses to ensure that the effect was not mediated by serum levels of thyroid-stimulating hormone, dihydroepiandosterone (DHEA) and DHEA sulfate, estradiol, testosterone, sex hormone–binding globulin (SHBG), or androstenedione.
This study was the first in this population to obtain and adjust for serum sex hormone and SHBG levels, said Dr. Muka.
The prospective design of the study and the long follow-up period were study strengths, said Dr. Muka. Additionally, blood glucose readings taken at study visits, together with electronically linked pharmacy dispensing records, were used for incident diabetes diagnoses.
Study limitations, Dr. Muka said, included the possibility of survival bias, since enrollees “may represent survivors of early menopause who did not develop [type 2 diabetes] or die prior to enrollment.” However, he said, this would mean that “we have underestimated the association, so the risk would be even higher.” Also, all study participants were white, so the results cannot be extrapolated to nonwhite populations.
Dr. Muka said that the largely American audience for his presentation was interested in the fact that the association existed independent of BMI, an obesity marker, based on questions and comments following the talk. “Indeed, we stratified the analysis, and we didn’t find any difference between participants who were obese and nonobese.” Also, he said that there were queries about whether the analyses had corrected for DEXA measurements, in order to assess lean versus fat body composition more accurately. This analysis has not been done, but Dr. Muka plans to complete it on his return to Rotterdam, he said.
Up to 10% of women will reach menopause before the age of 45, said Dr. Muka, so this analysis has the potential to impact primary care for millions of women. “Women who undergo early menopause may be a target for type 2 diabetes prevention measures and might need to be screened for other cardiovascular risk factors like high blood pressure and dyslipidemia, since they are also at risk for cardiovascular disease.”
Dr. Muka reported no outside funding sources and had no relevant financial disclosures.
koakes@frontlinemedcom.com
On Twitter @karioakes
“What we see in our data is that indeed, early onset of menopause is associated with increased risk of type 2 diabetes, and this association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also of estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, in an interview.
Dr. Muka, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands, presented the analysis from a large, prospective cohort of menopausal women at the annual meeting of the North American Menopause Society.
In an interview, Dr. Muka noted that the study investigated whether the association between early age at natural menopause (ANM) and type 2 diabetes is independent of intermediate risk factors for type 2 diabetes, such as obesity. Finally, the study also assessed whether endogenous sex hormone levels play a role in the link between early ANM and type 2 diabetes.
Enrollment in the Rotterdam study has been continuing in waves since the 1990s, with enrollment for participants in this particular study cohort occurring in 1997 and with additional cohorts enrolled in 2000-2001 and 2006-2008.
“I think this is the first prospective study with such long follow-up data and with a broad adjustment for confounding factors. Previous studies have been mainly cross-sectional, providing conflicting results,” said Dr. Muka.
Using self-reported age at menopause, the investigators excluded from the study women whose menopausal status was not known, who were actually not menopausal, or whose menopause had not occurred naturally. The study population also excluded women with prevalent type 2 diabetes or for whom no information about diabetes follow-up could be found.
The remaining 3,210 women who were included in the study had a median age of 67 years and had reached menopause at a median of 49.9 years. Most women (82.6%) had an ANM of 45-55 years; ANM for 8.8% was 40-44 years, while just 2.3% had an ANM of under 40 years. Mean body mass index was 27.1 kg/m2.
Participants were considered to have incident diabetes based on several sources: a general practitioner’s records, hospital discharge paperwork, or glucose measurements from visits during the Rotterdam study. Participants also were classified as having diabetes if they used a hypoglycemic medication or had a fasting blood glucose level of at least 7 mmol/L (126 mg/dL) or, in the absence of a fasting blood glucose measurement, a nonfasting blood glucose of at least 11.1 mmol/L (200 mg/dL).
Dr. Muka said he and his coinvestigators identified and adjusted for a large number of variables, using a series of three Cox proportion hazard models.
The first model adjusted for age, which wave of enrollment (cohort) participants were in, hormone therapy status, age at menarche, and the number of pregnancies that reached at least 6 months’ gestation.
The second model used all of the factors in model 1, and added BMI and glucose and insulin levels. The third model used all of the factors in model 2, and also added total cholesterol level, systolic blood pressure, the use of lipid-lowering or antihypertensive medications, alcohol and tobacco use, educational level, prevalent cardiovascular disease, and C-reactive protein levels.
The association of early ANM with the risk of type 2 diabetes was statistically significant in all three models (P less than .001), with very similar hazard ratios (HRs) in all models. For the third, the most comprehensive model, the HR was 1.42 (95% confidence interval, 0.83-2.45).
Extensive sensitivity analyses were carried out, and the association held independent of physical activity level, smoking status, use of hormone therapy, and age. The investigators also used multivariable analyses to ensure that the effect was not mediated by serum levels of thyroid-stimulating hormone, dihydroepiandosterone (DHEA) and DHEA sulfate, estradiol, testosterone, sex hormone–binding globulin (SHBG), or androstenedione.
This study was the first in this population to obtain and adjust for serum sex hormone and SHBG levels, said Dr. Muka.
The prospective design of the study and the long follow-up period were study strengths, said Dr. Muka. Additionally, blood glucose readings taken at study visits, together with electronically linked pharmacy dispensing records, were used for incident diabetes diagnoses.
Study limitations, Dr. Muka said, included the possibility of survival bias, since enrollees “may represent survivors of early menopause who did not develop [type 2 diabetes] or die prior to enrollment.” However, he said, this would mean that “we have underestimated the association, so the risk would be even higher.” Also, all study participants were white, so the results cannot be extrapolated to nonwhite populations.
Dr. Muka said that the largely American audience for his presentation was interested in the fact that the association existed independent of BMI, an obesity marker, based on questions and comments following the talk. “Indeed, we stratified the analysis, and we didn’t find any difference between participants who were obese and nonobese.” Also, he said that there were queries about whether the analyses had corrected for DEXA measurements, in order to assess lean versus fat body composition more accurately. This analysis has not been done, but Dr. Muka plans to complete it on his return to Rotterdam, he said.
Up to 10% of women will reach menopause before the age of 45, said Dr. Muka, so this analysis has the potential to impact primary care for millions of women. “Women who undergo early menopause may be a target for type 2 diabetes prevention measures and might need to be screened for other cardiovascular risk factors like high blood pressure and dyslipidemia, since they are also at risk for cardiovascular disease.”
Dr. Muka reported no outside funding sources and had no relevant financial disclosures.
koakes@frontlinemedcom.com
On Twitter @karioakes
“What we see in our data is that indeed, early onset of menopause is associated with increased risk of type 2 diabetes, and this association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also of estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, in an interview.
Dr. Muka, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands, presented the analysis from a large, prospective cohort of menopausal women at the annual meeting of the North American Menopause Society.
In an interview, Dr. Muka noted that the study investigated whether the association between early age at natural menopause (ANM) and type 2 diabetes is independent of intermediate risk factors for type 2 diabetes, such as obesity. Finally, the study also assessed whether endogenous sex hormone levels play a role in the link between early ANM and type 2 diabetes.
Enrollment in the Rotterdam study has been continuing in waves since the 1990s, with enrollment for participants in this particular study cohort occurring in 1997 and with additional cohorts enrolled in 2000-2001 and 2006-2008.
“I think this is the first prospective study with such long follow-up data and with a broad adjustment for confounding factors. Previous studies have been mainly cross-sectional, providing conflicting results,” said Dr. Muka.
Using self-reported age at menopause, the investigators excluded from the study women whose menopausal status was not known, who were actually not menopausal, or whose menopause had not occurred naturally. The study population also excluded women with prevalent type 2 diabetes or for whom no information about diabetes follow-up could be found.
The remaining 3,210 women who were included in the study had a median age of 67 years and had reached menopause at a median of 49.9 years. Most women (82.6%) had an ANM of 45-55 years; ANM for 8.8% was 40-44 years, while just 2.3% had an ANM of under 40 years. Mean body mass index was 27.1 kg/m2.
Participants were considered to have incident diabetes based on several sources: a general practitioner’s records, hospital discharge paperwork, or glucose measurements from visits during the Rotterdam study. Participants also were classified as having diabetes if they used a hypoglycemic medication or had a fasting blood glucose level of at least 7 mmol/L (126 mg/dL) or, in the absence of a fasting blood glucose measurement, a nonfasting blood glucose of at least 11.1 mmol/L (200 mg/dL).
Dr. Muka said he and his coinvestigators identified and adjusted for a large number of variables, using a series of three Cox proportion hazard models.
The first model adjusted for age, which wave of enrollment (cohort) participants were in, hormone therapy status, age at menarche, and the number of pregnancies that reached at least 6 months’ gestation.
The second model used all of the factors in model 1, and added BMI and glucose and insulin levels. The third model used all of the factors in model 2, and also added total cholesterol level, systolic blood pressure, the use of lipid-lowering or antihypertensive medications, alcohol and tobacco use, educational level, prevalent cardiovascular disease, and C-reactive protein levels.
The association of early ANM with the risk of type 2 diabetes was statistically significant in all three models (P less than .001), with very similar hazard ratios (HRs) in all models. For the third, the most comprehensive model, the HR was 1.42 (95% confidence interval, 0.83-2.45).
Extensive sensitivity analyses were carried out, and the association held independent of physical activity level, smoking status, use of hormone therapy, and age. The investigators also used multivariable analyses to ensure that the effect was not mediated by serum levels of thyroid-stimulating hormone, dihydroepiandosterone (DHEA) and DHEA sulfate, estradiol, testosterone, sex hormone–binding globulin (SHBG), or androstenedione.
This study was the first in this population to obtain and adjust for serum sex hormone and SHBG levels, said Dr. Muka.
The prospective design of the study and the long follow-up period were study strengths, said Dr. Muka. Additionally, blood glucose readings taken at study visits, together with electronically linked pharmacy dispensing records, were used for incident diabetes diagnoses.
Study limitations, Dr. Muka said, included the possibility of survival bias, since enrollees “may represent survivors of early menopause who did not develop [type 2 diabetes] or die prior to enrollment.” However, he said, this would mean that “we have underestimated the association, so the risk would be even higher.” Also, all study participants were white, so the results cannot be extrapolated to nonwhite populations.
Dr. Muka said that the largely American audience for his presentation was interested in the fact that the association existed independent of BMI, an obesity marker, based on questions and comments following the talk. “Indeed, we stratified the analysis, and we didn’t find any difference between participants who were obese and nonobese.” Also, he said that there were queries about whether the analyses had corrected for DEXA measurements, in order to assess lean versus fat body composition more accurately. This analysis has not been done, but Dr. Muka plans to complete it on his return to Rotterdam, he said.
Up to 10% of women will reach menopause before the age of 45, said Dr. Muka, so this analysis has the potential to impact primary care for millions of women. “Women who undergo early menopause may be a target for type 2 diabetes prevention measures and might need to be screened for other cardiovascular risk factors like high blood pressure and dyslipidemia, since they are also at risk for cardiovascular disease.”
Dr. Muka reported no outside funding sources and had no relevant financial disclosures.
koakes@frontlinemedcom.com
On Twitter @karioakes
Key clinical point: Early menopause is associated with an increased risk for type 2 diabetes.
Major finding: Age at menopause between 40 and 45 was associated with a relative risk of 1.49 for type 2 diabetes.
Data source: A prospective cohort study of an initial cohort of 3,210 menopausal women.
Disclosures: No outside funding source was reported. Dr. Muka reported having no relevant financial conflicts.
When is it time to stop hormone therapy?
Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.
Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.
And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.
And risk stratification also becomes relevant. Let’s say the patient is a slender white or Asian woman with a low body mass index , or she has a parent who had a hip fracture. Continuing low-dose systemic hormone therapy in this case, particularly for osteoporosis prevention when vasomotor symptoms are no longer present, might make sense. However, if the patient is obese, and, therefore has a lower risk for osteoporosis, it may be that ongoing use of systemic hormone therapy would not be indicated, and that patient should be encouraged to discontinue at that point.
Also, if a uterus is not present – and we’re talking only about estrogen therapy, given its greater safety profile with long-term use with respect to breast cancer – clinicians and women can be more comfortable with continued use of low-dose systemic hormone therapy for osteoporosis prevention. If a uterus is present, then women making decisions about long-term use of hormone therapy need to be aware of the small, but I believe real, elevated risk of breast cancer. With each office visit and when decisions about refilling prescriptions or continuing hormone therapy are made, this is an important issue to discuss, particularly if there’s an intact uterus. These discussions also need to be documented in the record.
What about the route of estrogen? Age, BMI, and oral estrogen therapy each represent independent risk factors for venous thromboembolism. For older, as well as obese menopausal women, who are candidates for systemic hormone therapy, I prefer transdermal over oral estrogen therapy.
Finally, I counsel women that although vasomotor symptoms/hot flashes improve as women age, the same is not true for genitourinary syndrome of menopause (GSM, also known as genital atrophy). If vaginal dryness, pain with sex, or other manifestations of GSM occur in women tapering their dose of systemic hormone therapy or in women who have discontinued systemic hormone therapy, initiation and long-term use of low-dose vaginal estrogen should be considered.
References
1. Menopause. 2014 Jun;21(6):679-81.
Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.
Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.
Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.
And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.
And risk stratification also becomes relevant. Let’s say the patient is a slender white or Asian woman with a low body mass index , or she has a parent who had a hip fracture. Continuing low-dose systemic hormone therapy in this case, particularly for osteoporosis prevention when vasomotor symptoms are no longer present, might make sense. However, if the patient is obese, and, therefore has a lower risk for osteoporosis, it may be that ongoing use of systemic hormone therapy would not be indicated, and that patient should be encouraged to discontinue at that point.
Also, if a uterus is not present – and we’re talking only about estrogen therapy, given its greater safety profile with long-term use with respect to breast cancer – clinicians and women can be more comfortable with continued use of low-dose systemic hormone therapy for osteoporosis prevention. If a uterus is present, then women making decisions about long-term use of hormone therapy need to be aware of the small, but I believe real, elevated risk of breast cancer. With each office visit and when decisions about refilling prescriptions or continuing hormone therapy are made, this is an important issue to discuss, particularly if there’s an intact uterus. These discussions also need to be documented in the record.
What about the route of estrogen? Age, BMI, and oral estrogen therapy each represent independent risk factors for venous thromboembolism. For older, as well as obese menopausal women, who are candidates for systemic hormone therapy, I prefer transdermal over oral estrogen therapy.
Finally, I counsel women that although vasomotor symptoms/hot flashes improve as women age, the same is not true for genitourinary syndrome of menopause (GSM, also known as genital atrophy). If vaginal dryness, pain with sex, or other manifestations of GSM occur in women tapering their dose of systemic hormone therapy or in women who have discontinued systemic hormone therapy, initiation and long-term use of low-dose vaginal estrogen should be considered.
References
1. Menopause. 2014 Jun;21(6):679-81.
Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.
Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.
Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.
And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.
And risk stratification also becomes relevant. Let’s say the patient is a slender white or Asian woman with a low body mass index , or she has a parent who had a hip fracture. Continuing low-dose systemic hormone therapy in this case, particularly for osteoporosis prevention when vasomotor symptoms are no longer present, might make sense. However, if the patient is obese, and, therefore has a lower risk for osteoporosis, it may be that ongoing use of systemic hormone therapy would not be indicated, and that patient should be encouraged to discontinue at that point.
Also, if a uterus is not present – and we’re talking only about estrogen therapy, given its greater safety profile with long-term use with respect to breast cancer – clinicians and women can be more comfortable with continued use of low-dose systemic hormone therapy for osteoporosis prevention. If a uterus is present, then women making decisions about long-term use of hormone therapy need to be aware of the small, but I believe real, elevated risk of breast cancer. With each office visit and when decisions about refilling prescriptions or continuing hormone therapy are made, this is an important issue to discuss, particularly if there’s an intact uterus. These discussions also need to be documented in the record.
What about the route of estrogen? Age, BMI, and oral estrogen therapy each represent independent risk factors for venous thromboembolism. For older, as well as obese menopausal women, who are candidates for systemic hormone therapy, I prefer transdermal over oral estrogen therapy.
Finally, I counsel women that although vasomotor symptoms/hot flashes improve as women age, the same is not true for genitourinary syndrome of menopause (GSM, also known as genital atrophy). If vaginal dryness, pain with sex, or other manifestations of GSM occur in women tapering their dose of systemic hormone therapy or in women who have discontinued systemic hormone therapy, initiation and long-term use of low-dose vaginal estrogen should be considered.
References
1. Menopause. 2014 Jun;21(6):679-81.
Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.
Breast arterial calcifications predict atherosclerotic cardiovascular events
Longitudinal results of a prospective study of women with and without breast arterial calcifications showed that women with the calcifications were significantly more likely to have atherosclerotic cardiovascular events than were women without them.
In a 10-year follow-up of a cohort of women receiving screening mammograms, women who did not have cardiovascular disease at baseline and were positive for breast arterial calcifications (BACs) were three times more likely to develop atherosclerotic cardiovascular disease (ASCVD) as those who were BAC negative at baseline (9.8% vs. 3.3%; P = .001).
These results paralleled those found 5 years previously among the cohort. At that point, 6.3% of the BAC-positive group developed ASCVD, compared with 2.3% of the BAC-negative group (P = .003). At 10 years, “multiple logistic regression analysis found BAC to be strongly associated with ASCVD events, with an odds ratio of 2.29,” senior investigator Peter Schnatz, DO, said in an interview.
Based on these results, Dr. Schnatz and his coinvestigators are suggesting that BACs be routinely reported on mammograms and viewed as a marker for the development of cardiovascular disease.
Presenting the unpublished 10-year findings at the annual meeting of the North American Menopause Society, Dr. Schnatz, the society’s 2015-2016 president, said that the BAC-positive group was also more likely to develop risk factors for ASCVD (86.8% vs. 76.3; P = .01).
These risk factors were age, hypertension, hypercholesterolemia, diabetes, and menopause. The other results were significant after the investigators controlled for age, so the increased risk was not merely caused by the passage of time and the normal aging process.
The prospective study compared age-matched controls with and without BACs to determine whether BACs seen on routine mammography can predict the development of ASCVD, by tracking the presence of BACs and gathering information about ASCVD risk factors and events via patient self-report in an annual questionnaire. The events that were considered ASCVD markers were angina, myocardial infarction, an abnormal angiogram, coronary artery bypass grafting, and stroke.
The initial baseline study upon which the longitudinal prospective studies are based gathered data from 1,919 women with a median age of 56, plus or minus 12.7 years (range, 25-96), to determine whether women with BAC had an increased frequency of cardiovascular disease risk factors, and of ASCVD. Baseline findings showed an independent association of BAC with multiple risk factors and with ASCVD events, even after age was controlled for.
Dr. Schnatz, who is a professor of ob.gyn. and internal medicine at Thomas Jefferson University, Philadelphia, said in his presentation that BACs “appear to be a risk indicator of the presence of ASCVD. More importantly, in this first prospective analysis of BAC as a risk predictor, BAC appears to be a risk predictor for the future development of ASCVD.”
Patients were considered BAC positive if their mammograms showed BAC on at least one of two standard views of either or both breasts. The screening mammograms were read in a uniform fashion by 1 of 21 radiologists, who used identical and well-accepted criteria for BACs. Overall, 268 women (14%) were BAC positive, in line with the 9%-17.5% prevalence reported in the literature, Dr. Schnatz said.
BACs are diffuse calcifications of the arterial tunica media, which are common but often unreported by radiologists who find them on screening mammograms, though they are seen in up to 17.5% of mammograms.
Medial arterial calcifications, such as BACs, are fine-grained deposits seen in small- to medium-sized muscular arteries. Though they have been observed for some time, their significance has been unknown, and they are often seen as part of the normal aging process, Dr. Schnatz said. With the advent of newer mammography technology in the 2000s, much smaller calcifications could be seen, and research into the significance of BACs detected on screening mammogram was revived and refined, he said.
“If BAC has value as a marker for coronary artery disease, then mammograms could be a practical tool for detecting CAD risk in women,” Dr. Schnatz said. “This might contribute to earlier detection of vascular damage, especially important in women at high risk of CAD or with unrecognized heart disease.”
Dr. Schnatz said he plans to incorporate BAC status into validated cardiovascular risk predictors, and see how a prediction model that includes BAC fares.
Dr. Schnatz reported having no relevant financial disclosures.
koakes@frontlinemedcom.com
On Twitter @karioakes
Longitudinal results of a prospective study of women with and without breast arterial calcifications showed that women with the calcifications were significantly more likely to have atherosclerotic cardiovascular events than were women without them.
In a 10-year follow-up of a cohort of women receiving screening mammograms, women who did not have cardiovascular disease at baseline and were positive for breast arterial calcifications (BACs) were three times more likely to develop atherosclerotic cardiovascular disease (ASCVD) as those who were BAC negative at baseline (9.8% vs. 3.3%; P = .001).
These results paralleled those found 5 years previously among the cohort. At that point, 6.3% of the BAC-positive group developed ASCVD, compared with 2.3% of the BAC-negative group (P = .003). At 10 years, “multiple logistic regression analysis found BAC to be strongly associated with ASCVD events, with an odds ratio of 2.29,” senior investigator Peter Schnatz, DO, said in an interview.
Based on these results, Dr. Schnatz and his coinvestigators are suggesting that BACs be routinely reported on mammograms and viewed as a marker for the development of cardiovascular disease.
Presenting the unpublished 10-year findings at the annual meeting of the North American Menopause Society, Dr. Schnatz, the society’s 2015-2016 president, said that the BAC-positive group was also more likely to develop risk factors for ASCVD (86.8% vs. 76.3; P = .01).
These risk factors were age, hypertension, hypercholesterolemia, diabetes, and menopause. The other results were significant after the investigators controlled for age, so the increased risk was not merely caused by the passage of time and the normal aging process.
The prospective study compared age-matched controls with and without BACs to determine whether BACs seen on routine mammography can predict the development of ASCVD, by tracking the presence of BACs and gathering information about ASCVD risk factors and events via patient self-report in an annual questionnaire. The events that were considered ASCVD markers were angina, myocardial infarction, an abnormal angiogram, coronary artery bypass grafting, and stroke.
The initial baseline study upon which the longitudinal prospective studies are based gathered data from 1,919 women with a median age of 56, plus or minus 12.7 years (range, 25-96), to determine whether women with BAC had an increased frequency of cardiovascular disease risk factors, and of ASCVD. Baseline findings showed an independent association of BAC with multiple risk factors and with ASCVD events, even after age was controlled for.
Dr. Schnatz, who is a professor of ob.gyn. and internal medicine at Thomas Jefferson University, Philadelphia, said in his presentation that BACs “appear to be a risk indicator of the presence of ASCVD. More importantly, in this first prospective analysis of BAC as a risk predictor, BAC appears to be a risk predictor for the future development of ASCVD.”
Patients were considered BAC positive if their mammograms showed BAC on at least one of two standard views of either or both breasts. The screening mammograms were read in a uniform fashion by 1 of 21 radiologists, who used identical and well-accepted criteria for BACs. Overall, 268 women (14%) were BAC positive, in line with the 9%-17.5% prevalence reported in the literature, Dr. Schnatz said.
BACs are diffuse calcifications of the arterial tunica media, which are common but often unreported by radiologists who find them on screening mammograms, though they are seen in up to 17.5% of mammograms.
Medial arterial calcifications, such as BACs, are fine-grained deposits seen in small- to medium-sized muscular arteries. Though they have been observed for some time, their significance has been unknown, and they are often seen as part of the normal aging process, Dr. Schnatz said. With the advent of newer mammography technology in the 2000s, much smaller calcifications could be seen, and research into the significance of BACs detected on screening mammogram was revived and refined, he said.
“If BAC has value as a marker for coronary artery disease, then mammograms could be a practical tool for detecting CAD risk in women,” Dr. Schnatz said. “This might contribute to earlier detection of vascular damage, especially important in women at high risk of CAD or with unrecognized heart disease.”
Dr. Schnatz said he plans to incorporate BAC status into validated cardiovascular risk predictors, and see how a prediction model that includes BAC fares.
Dr. Schnatz reported having no relevant financial disclosures.
koakes@frontlinemedcom.com
On Twitter @karioakes
Longitudinal results of a prospective study of women with and without breast arterial calcifications showed that women with the calcifications were significantly more likely to have atherosclerotic cardiovascular events than were women without them.
In a 10-year follow-up of a cohort of women receiving screening mammograms, women who did not have cardiovascular disease at baseline and were positive for breast arterial calcifications (BACs) were three times more likely to develop atherosclerotic cardiovascular disease (ASCVD) as those who were BAC negative at baseline (9.8% vs. 3.3%; P = .001).
These results paralleled those found 5 years previously among the cohort. At that point, 6.3% of the BAC-positive group developed ASCVD, compared with 2.3% of the BAC-negative group (P = .003). At 10 years, “multiple logistic regression analysis found BAC to be strongly associated with ASCVD events, with an odds ratio of 2.29,” senior investigator Peter Schnatz, DO, said in an interview.
Based on these results, Dr. Schnatz and his coinvestigators are suggesting that BACs be routinely reported on mammograms and viewed as a marker for the development of cardiovascular disease.
Presenting the unpublished 10-year findings at the annual meeting of the North American Menopause Society, Dr. Schnatz, the society’s 2015-2016 president, said that the BAC-positive group was also more likely to develop risk factors for ASCVD (86.8% vs. 76.3; P = .01).
These risk factors were age, hypertension, hypercholesterolemia, diabetes, and menopause. The other results were significant after the investigators controlled for age, so the increased risk was not merely caused by the passage of time and the normal aging process.
The prospective study compared age-matched controls with and without BACs to determine whether BACs seen on routine mammography can predict the development of ASCVD, by tracking the presence of BACs and gathering information about ASCVD risk factors and events via patient self-report in an annual questionnaire. The events that were considered ASCVD markers were angina, myocardial infarction, an abnormal angiogram, coronary artery bypass grafting, and stroke.
The initial baseline study upon which the longitudinal prospective studies are based gathered data from 1,919 women with a median age of 56, plus or minus 12.7 years (range, 25-96), to determine whether women with BAC had an increased frequency of cardiovascular disease risk factors, and of ASCVD. Baseline findings showed an independent association of BAC with multiple risk factors and with ASCVD events, even after age was controlled for.
Dr. Schnatz, who is a professor of ob.gyn. and internal medicine at Thomas Jefferson University, Philadelphia, said in his presentation that BACs “appear to be a risk indicator of the presence of ASCVD. More importantly, in this first prospective analysis of BAC as a risk predictor, BAC appears to be a risk predictor for the future development of ASCVD.”
Patients were considered BAC positive if their mammograms showed BAC on at least one of two standard views of either or both breasts. The screening mammograms were read in a uniform fashion by 1 of 21 radiologists, who used identical and well-accepted criteria for BACs. Overall, 268 women (14%) were BAC positive, in line with the 9%-17.5% prevalence reported in the literature, Dr. Schnatz said.
BACs are diffuse calcifications of the arterial tunica media, which are common but often unreported by radiologists who find them on screening mammograms, though they are seen in up to 17.5% of mammograms.
Medial arterial calcifications, such as BACs, are fine-grained deposits seen in small- to medium-sized muscular arteries. Though they have been observed for some time, their significance has been unknown, and they are often seen as part of the normal aging process, Dr. Schnatz said. With the advent of newer mammography technology in the 2000s, much smaller calcifications could be seen, and research into the significance of BACs detected on screening mammogram was revived and refined, he said.
“If BAC has value as a marker for coronary artery disease, then mammograms could be a practical tool for detecting CAD risk in women,” Dr. Schnatz said. “This might contribute to earlier detection of vascular damage, especially important in women at high risk of CAD or with unrecognized heart disease.”
Dr. Schnatz said he plans to incorporate BAC status into validated cardiovascular risk predictors, and see how a prediction model that includes BAC fares.
Dr. Schnatz reported having no relevant financial disclosures.
koakes@frontlinemedcom.com
On Twitter @karioakes
FROM THE NAMS 2016 ANNUAL MEETING
Key clinical point:
Major finding: BAC-positive women were three times more likely to develop ASCVD than were BAC-negative women (9.8% vs. 3.3%; P = .001)
Data source: A prospective longitudinal study of an initial cohort of 1,919 women receiving screening mammograms.
Disclosures: No outside funding source was reported. Dr. Schnatz reported having no relevant financial disclosures.